Influenza viruses are constantly changing and vaccines are reformulated every year. Accurately estimating influenza vaccine effectiveness to prevent influenza infection is critical in order to evaluate the protection provided by annual, nationwide vaccination programs. The discovery of more advanced strategies to measure vaccine effectiveness will potentially reduce the overall burden of influenza while improving the health of the population. We plan to systematically evaluate the effectiveness of influenza vaccines with the ACIP recommended universal immunization strategy for persons ages 6 months or older in the Scott and White Healthcare-Temple Population Research Area (SWH-TPRA) source population. Our objective is to use our singular research experience to explore current methodologies to measure vaccine effectiveness against lab- confirmed influenza (VE-LCI), and identify, implement and evaluate innovative, feasible, and sustainable strategies for measuring VE-LCI in all persons ages 6 months or older in outpatient acute care settings. Our central hypothesis is that timely and efficient measurement of VE-LCI is feasible and sustainable in the U.S. This hypothesis will be tested by pursuing three specific aims: 1) Identify innovative, feasible, and sustainable strategies to measure VE-LCI in a timely and efficient manner for persons of ages 6 months or older seeking care for an acute respiratory illness (ARI) in outpatient acute care settings, 2) Implement innovative, feasible and sustainable strategies to measure VE-LCI in a timely and efficient manner for persons 6 months or older seeking care for an ARI in outpatient acute care settings, and 3) Evaluate innovative, feasible and sustainable strategies to measure VE-LCI in a timely and efficient manner for persons 6 months or older seeking care for an ARI in outpatient acute care settings. To accomplish these goals, VE-LCI will be determined in children ages 6 months - 18 years, adults ages 19-49 years and those 50 years or older who present at SWH-TPRA outpatient acute care setting with a well-defined ARI cluster and test positive for influenza A or B by RT-PCR assay, by comparing their odds of being vaccinated against influenza with age-matched controls who had a negative influenza RT-PCR assay, after adjusting for confounders. During 2011-2012 through 2015-2016, persons from the SWH-TPRA source population, who have a PCP at SWH, and present with an ARI cluster during the influenza epidemic period at a SWH-TPRA outpatient clinic, urgent care or emergency department, will be eligible to participate in this CDC VE-LCI study, using a rolling 4 hour block recruitment strategy minimizing selection bias. Using RT-PCR confirmed case-control design, we will measure VE-LCI in all persons ages 6 months or older. Influenza immunization rates will be calculated for the RT-PCR confirmed cases and RT-PCR negative controls, adjusting VE-LCI for confounders. The proposed research is innovative, because it will greatly help understand timely and efficient measures of VE-LCI and will also define effective measures of the public health impact of expanded and increasing influenza immunization on burden of illness.